DESCRIPTION(adapted from applicant's abstract): Single nerve cells are often unreliable: repeated presentations of identical stimuli can generate significantly different trains of action potentials. Because this response variability limits the accuracy of encoding by the nervous system, its biophysical underpinnings are of great interest. The immediate goal of this project is to understand how two major sources of neuronal noise - synaptic noise in the signal received from presynaptic cells and channel noise caused by the probabilistic gating of ion channels - contribute to and interact with the dynamics of excitatory neurons of the hippocampal formation, a brain region implicated in learning and memory. Excitatory neurons of the medial entorhinal cortex (MEC) and hippocarnpus provide a powerful test-bed for these experiments for several reasons. For example: some of these neurons exhibit prominent channel noise that may limit response reliability and shape network responses; different classes of these neurons have contrasting rhythmic properties that imply contrasting stimulus preferences under noisy conditions; and these neurons play a critical role in human memory in the healthy and compromised brain. Electrophysiological experiments will be conducted using standard methods and newly developed stochastic dynamic clamp technology. The latter approach allows direct exploration of the causal roles of specific biological noise sources in shaping neuronal electrical dynamics and reliability. Four hypotheses will be tested: A. Excitatory neurons in MEC and hippocampus exhibit significant levels of channel noise B. Properties of reliability differ significantly among principal cells of the hippocampal formation C. Channel and synaptic noise influence electrical dynamics and reliability in the MEC D. Biological noise influences the behavior of biologically-inspired network simulations The long-term goal of this project - to enhance our understanding of how molecular-level events contribute to excitability, rhythmicity, and encoding properties in nerve cells - is important for improving human health. A mechanistic understanding of this connection may lead to novel diagnoses and treatments for several debilitating neurological disorders that disrupt the information-processing capabilities of the hippocampal region, including temporal-lobe epilepsy and stroke-related cell death.